1-236409068-TAAAAAA-TAAAAA

Variant names:

• chr1-236409068-TA-T
• rs772223735
• NM_145861.4:c.62-129delA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_145861.4(EDARADD):​c.62-129delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 202,838 control chromosomes in the GnomAD database, including 35 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 28)
  • Exomes 𝑓: 0.25 (35 hom.)
  • Failed GnomAD Quality Control
• Consequence: EDARADD NM_145861.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.336
• Publications: 0 publications found

Genes affected

EDARADD (HGNC:14341): (EDAR associated via death domain) This gene was identified by its association with ectodermal dysplasia, a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands. The protein encoded by this gene is a death domain-containing protein, and is found to interact with EDAR, a death domain receptor known to be required for the development of hair, teeth and other ectodermal derivatives. This protein and EDAR are coexpressed in epithelial cells during the formation of hair follicles and teeth. Through its interaction with EDAR, this protein acts as an adaptor, and links the receptor to downstream signaling pathways. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

EDARADD Gene-Disease associations (from GenCC):

• ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant hypohidrotic ectodermal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hypohidrotic ectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 35 SD,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145861.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDARADD	NM_145861.4	MANE Select	c.62-129delA		intron	N/A	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_080738.5		c.32-129delA		intron	N/A	NP_542776.1	Q8WWZ3-2
	EDARADD	NM_001422628.1		c.-5-129delA		intron	N/A	NP_001409557.1	A0A1B0GV26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDARADD	ENST00000334232.9	TSL:1 MANE Select	c.62-147delA		intron	N/A	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000359362.6	TSL:1	c.32-147delA		intron	N/A	ENSP00000352320.4	Q8WWZ3-2
	EDARADD	ENST00000637660.1	TSL:5	c.-5-147delA		intron	N/A	ENSP00000490347.1	A0A1B0GV26

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 555 AN: 129096 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00159

Gnomad EAS AF: 0.00227

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00906

GnomAD4 exome AF: 0.254 AC: 51474 AN: 202838 Hom.: 35 AF XY: 0.257 AC XY: 27336 AN XY: 106460

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.213 AC: 979 AN: 4606

American (AMR) AF: 0.268 AC: 1901 AN: 7092

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 1579 AN: 5870

East Asian (EAS) AF: 0.282 AC: 4395 AN: 15608

South Asian (SAS) AF: 0.275 AC: 3235 AN: 11748

European-Finnish (FIN) AF: 0.195 AC: 3822 AN: 19574

Middle Eastern (MID) AF: 0.247 AC: 213 AN: 862

European-Non Finnish (NFE) AF: 0.257 AC: 32466 AN: 126388

Other (OTH) AF: 0.260 AC: 2884 AN: 11090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00429 AC: 554 AN: 129094 Hom.: 1 Cov.: 28 AF XY: 0.00554 AC XY: 342 AN XY: 61774

African (AFR) AF: 0.00269 AC: 94 AN: 34910

American (AMR) AF: 0.00374 AC: 47 AN: 12554

Ashkenazi Jewish (ASJ) AF: 0.00159 AC: 5 AN: 3144

East Asian (EAS) AF: 0.00227 AC: 10 AN: 4400

South Asian (SAS) AF: 0.0248 AC: 100 AN: 4034

European-Finnish (FIN) AF: 0.0191 AC: 130 AN: 6810

Middle Eastern (MID) AF: 0.00752 AC: 2 AN: 266

European-Non Finnish (NFE) AF: 0.00248 AC: 150 AN: 60396

Other (OTH) AF: 0.00902 AC: 16 AN: 1774

Alfa AF: 0.000274 Hom.: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772223735; hg19: chr1-236572368; COSMIC: COSV62064697;